Rolien Bosch (1), Kirsten Bergmann (1), Paul Baverel (2), David Fairman (2)*, Peter Vis (1), Balaji Agoram (2)
1 LAP&P Consultants BV, 2 MedImmune, Cambridge, UK *Current affiliation: GSK, Stevenage, UK
Objectives: To develop a mathematical model that describes the effect of IV administration of recombinant human Lecithin-cholesterol acyltransferase (rhLCAT) and HDL mimetics on biomarkers of reverse cholesterol transport (RCT) in humans.
Methods: The systems model was built using NONMEM v.7 with clinical data combining in-house individual rhLCAT [1,2] exposure, lipid biomarkers (high density lipoprotein-cholesterol HDLc, and cholesteryl-ester CE) and summary level data of HDL mimetics derived from literature [3,4,5]. The model was evaluated using VPCs plus sensitivity analyses and was externally qualified using two independent clinical studies of HDL mimetics [5, 6].
Results: Although stimulation of RCT by HDL mimetics and rhLCAT are related to different mechanisms of action, the developed eight compartment mechanistic model was able to adequately describe both the observed plasma rhLCAT concentrations and the time-course of relevant biomarkers, including the fraction of esterified and unesterified cholesterol within HDL particles. Both internal and external model validation using VPC showed adequate model fit and good predictive performance. HDLc AUC showed high correlation with the amount of cholesterol movement from the peripheral tissue and can be used to compare the effects of HDL mimetics with rhLCAT on RCT.
Conclusions: We have generated a model that describes the time-dependent dynamics of lipid biomarkers within HDL particles by integrating literature and study data from two compounds with different mechanisms of action. This is the first to integrate the effects of HDL mimetics and rhLCAT preparations on RCT and describes both the conformational change of the HDL particle from pre-β-HDL to αHDL as well as the effect of this conformational change on the efflux of cholesterol.
References:
[1] www.clinicaltrials.gov: NCT01554800
[2] Poster Noordwijkerhout
[3] Nanjee MN, Cooke CJ, Garvin R, Semeria F, Lewis G, Olszewski WL, Miller NE., Intravenous apoA-I/lecithin discs increase pre-beta-HDL concentration in tissue fluid and stimulate reverse cholesterol transport in humans., J Lipid Res. 2001 Oct;42(10):1586-93.
[4] Kujiraoka T, Nanjee MN, Oka T, Ito M, Nagano M, Cooke CJ, Takahashi S, Olszewski WL, Wong JS, Stepanova IP, Hamilton RL, Egashira T, Hattori H, Miller NE. Effects of intravenous apolipoprotein A-I/phosphatidylcholine discs on LCAT, PLTP, and CETP in plasma and peripheral lymph in humans. Arterioscler Thromb Vasc Biol. 2003 Sep 1;23(9):1653-9. Epub 2003 Jul 31.
[5] Gille A, Easton R, D’Andrea D, Wright SD, Shear CL., CSL112 enhances biomarkers of reverse cholesterol transport after single and multiple infusions in healthy subjects., Arterioscler Thromb Vasc Biol. 2014 Sep;34(9):2106-14. doi: 10.1161/ATVBAHA.114.303720. Epub 2014 Jun 26.
[6] www.clinicaltrials.gov: NCT01499420
Reference: PAGE 24 () Abstr 3392 [www.page-meeting.org/?abstract=3392]
Poster: Drug/Disease modeling - Other topics